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Preterm infants have a high rate of neurodevelopmental handicap. Recent imaging studies have revealed that adverse outcomes are strongly associated with reduced brain growth and neural complexity in later life. Increasing data suggest that these chronic deficits primarily reflect acute neuronal and glial injury sustained during adverse in utero events, such as exposure to severe hypoxia-ischemia and inflammation. In the present review we examine recent evidence that this chronic impairment is partly due to upregulation of physiological apoptosis, related to input deprivation, and output isolation secondary to acute white and gray matter damage and axonal injury. However, progenitor cells in the subventricular zone (SVZ) are also vulnerable to injury, and loss of part of this critical population likely further compromises brain development. Based on these concepts the impact of proposed interventions such as induced hypothermia and endogenous growth factors are likely to be complex, but potentially offer focused ways of improving the outcomes of premature birth.

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Fetal exposure to inflammatory mediators is associated with a greater risk of brain injury and may cause endothelial dysfunction; however, nearly all the evidence is derived from gram-negative bacteria. Intrapleural injections of OK-432, a killed Su-strain of Streptococcus pyogenes, has been used to treat fetal chylothorax. In this study, we evaluated the neural and cardiovascular effects of OK-432 in preterm fetal sheep (104 +/- 1 days, term 147 days). OK-432 (0.1 mg, n = 6) or saline vehicle (n = 7) was infused in the fetal pleura, and fetuses were monitored for 7 days. Blood samples were taken routinely for plasma nitrite measurement. Fetal brains were taken for histological assessment at the end of the experiment. Between 3 and 7 h postinjection, OK-432 administration was associated with transient suppression of fetal body and breathing movements and electtroencephalogram activity (P < 0.05), increased carotid and femoral vascular resistance (P < 0.05), but no change in blood pressure. Brain activity and behavior then returned to normal except in one fetus that developed seizures. OK-432 fetuses showed progressive, sustained vasodilatation (P < 0.05), with lower blood pressure after 4 days (P < 0.05), but normal heart rate. There were no changes in plasma nitrite levels. Histological studies showed bilateral infarction in the dorsal limb of the hippocampus of the fetus that developed seizures, but no injury in other fetuses. We conclude that a single low-dose injection of OK-432 can be associated with risk of focal cerebral injury in the preterm fetus and chronic central and peripheral vasodilatation that does not appear to be mediated by nitric oxide.

Plasma samples were taken during and after UCO. Fetal extradural and esophageal temperatures, mean arterial blood pressure, and Background and Purpose-Hypothermia induced after perinatal hypoxia-ischemia is partially protective. This study examined whether early treatment with the noncompetitive N-methyl-d-aspartate receptor antagonist, dizocilpine, can augment neuroprotection with delayed hypothermia after severe asphyxia in preterm fetal sheep at 0.7 weeks gestation (equivalent to 28-32 weeks in humans). Methods-Fifty minutes after umbilical cord occlusion for 25 minutes, fetuses were randomized to either dizocilpine (2 mg/kg estimated fetal weight intravenously, then 0.07 mg/kg/h for 4 hours) and then after 5.5 hours to wholebody cooling to 3°C below baseline, or sham cooling, until 72 hours, and euthanized 7 days after umbilical cord occlusion. Results-Delayed hypothermia was associated with improved neuronal survival (P<0.02) and reduced microglia (P=0.004) and caspase-3-positive cells (P<0.01) compared with umbilical cord occlusion. Dizocilpine was associated with reduced microglia (P<0.05) but no effect on caspase-3 induction and improved survival only in CA1/2 (P<0.05) with no apparent additive effect with delayed hypothermia. Conclusions-Early Histological AnalysisCell counts of brain sections stained for NeuN (neuronal survival), cleaved caspase-3 (a measure of apopotosis), and Isolectin B4 (IB4, activated microglia) were performed in the caudate nucleus and putamen and in the CA1/2 and CA3 regions of the hippocampus using stereological principles ( online-only Data Supplement Figure I). Statistical AnalysisData were analyzed using mixed model analysis of variance followed by the Tukey post hoc test if a significant effect was found. Data are mean±SEM. Results Blood CompositionThere were no significant differences in baseline blood gases, pH, glucose, or lactate concentrations before UCO ( online-only Data Supplement Table I). UCO was associated with hypoxemia and severe mixed respiratory and metabolic acidosis, which resolved after release of UCO. Subsequently, Pao 2 was higher in the UCO groups than sham controls. Hypothermia was associated with a small increase in pH and glucose levels that resolved after rewarming. TemperatureExtradural and esophageal temperatures increased during dizocilpine infusion from 1 to 5 hours after UCO (P<0.05; online-only Data Supplement Figure II). Cooling was associated with significantly reduced temperatures from 5.5 to 72 hours (P<0.05). Mean Arterial Blood PressureUCO was associated with profound hypotension followed by rebound hypertension from 1 to 2 hours compared to sham controls (P<0.05; online-only Data Supplement Figure II) with no subsequent between-group differences. Electroencephalographic Power (dB) and Electrographic SeizuresUCO was associated with suppressed electroencephalographic power compared with sham controls from 0.5 to 72 hours after UCO (P<0.05) followed by progressive recovery ( online-only Data Supplement Figure II), which was similar betwee...

At 103 to 104 days gestation, fetuses were randomly assigned to sham occlusion followed by normothermia (sham-normothermia, n=8), or whole-body cooling for 72 hours (sham-hypothermia, n=8), or umbilical cord occlusion for 25 minutes, followed by sham hypothermia (occlusion-normothermia, n=12), or whole-body cooling started from 30 minutes (occlusion-early hypothermia, n=10), or 5 hours (occlusion-delayed hypothermia, n=7) after occlusion and continued for 72 hours. Mild whole-body cooling was induced by circulating cold water through the cooling coil. Seven days after occlusion, the ewes and fetuses were killed.Mean arterial pressure, blood gases, EEG activity, and temperature were recorded throughout the experiment. EEG power and spectral Background and Purpose-Electroencephalographic recovery is predictive of outcome after perinatal hypoxia-ischemia, but it is unknown whether early changes in electroencephalographic can predict the response to therapeutic hypothermia in the preterm brain. Methods-0.7 gestation fetal sheep received umbilical cord occlusion or sham occlusion for 25 minutes, followed by sham hypothermia or whole-body cooling started either 30 minutes or 5 hours after occlusion and continued for 72 hours. Results-Early but not delayed hypothermia reduced neuronal loss and microglial induction in the striatum, with faster recovery of spectral edge frequency, reduced seizure burden, and less suppression of electroencephalographic amplitude (P<0.05). Conclusions-Recovery ImmunohistochemistryBrain sections were stained for NeuN (neuronal survival) and IB4 (activated microglia) in the caudate nucleus and putamen, and positive cells were counted stereologically. Statistical AnalysisData were evaluated by repeated measures ANCOVA (SPSS v22, SPSS Inc, IL) and Sidak post hoc analysis. The within subjects' correlation was assessed between EEG amplitude (μV) and extradural temperature. Statistical significance was accepted at P<0.05. Results Blood Composition, Arterial Pressure, and Extradural TemperatureUmbilical cord occlusion was associated with profound hypoxia, mixed metabolic and respiratory acidosis, and hypotension, with rapid recovery after release of occlusion. Hypothermia was associated with a small increase in pH and glucose and a lower PaCO 2 compared with occlusion-normothermia (Table I in the online-only Data Supplement) and no effect on mean arterial pressure (Table II in EEG Power and SEFOcclusion was associated with suppressed EEG power until 84 hours after asphyxia in the occlusion-normothermia group and 72 hours in both hypothermia groups (P<0.05; versus sham-normothermia; Figure 1). Compared with occlusionnormothermia, EEG power was reduced from 1 to 12 hours with early hypothermia, and 6 to 12 hours with delayed hypothermia (P<0.05). Delayed hypothermia was associated with suppressed EEG power compared with early hypothermia from 24 to 30 hours (P<0.05). SEF was significantly suppressed with occlusion-normothermia until 72 hours after occlusion compared with sham-normothermia (P<0.05;...

Historical, widespread use of clinics such as these with anecdotal reports of extraordinary survival merit prospective, systematic monitoring of patient outcomes. For data to be meaningful, however, disease status must be pathologically confirmed and patient follow-up improved.